a study to evaluate the pharmacokinetics, pharmacodynamics and safety of asp8232 in subjects with renal impairment and in type 2 diabetes mellitus subjects with chronic kidney disease

Conditions: Healthy Subjects; Pharmacokinetics of ASP8232; Pharmacodynamics of ASP8232; Chronic Kidney Disease (CKD); Type 2 Diabetes Mellitus (T2DM)

Summary: this study consists of two parts. part 1 evaluates the effect of renal impairment on the pk and pd of a single dose of asp8232. in addition, the safety and tolerability will be assessed. part 2 evaluates the pk, pd, and safety and tolerability of multiple doses of asp8232 compared with placebo in type 2 diabetes mellitus (t2dm) subjects with chronic kidney disease (ckd).

this is a two-part study. part 1 compares the pharmacokinetics (pk), pharmacodynamics (pd) and safety and tolerability of asp8232 in healthy subjects with subjects with different degrees of renal impairment; part 2 is a multiple-dose, placebo-controlled study to evaluate the pk, pd and safety and tolerability of multiple doses of asp8232 in t2dm subjects with ckd. part 1: subjects reside in the clinic for 9 days, receiving a single oral dose of asp8232 on day 1 under fasted conditions followed by a 168-hours blood and urine pk/pd sampling period. subjects are discharged on day 8 and return to the clinic on days 10, 12, 14, 21, 28, and 42 for the collection of blood pk/pd samples. an end of study visit (esv) takes place after the last pk sample is collected on day 56. part 2: subjects are admitted to the clinic on day -2 in order to collect pd urine samples before dosing begins on day 1. subjects receive multiple oral doses of asp8232 or placebo for 28 days. they are discharged on day 8 and return to the clinic on days 14 and 21, and days 27 to 29 for blood pk/pd and urine pd samples. an esv takes place 14 to 28 days after the last pk/pd sample is collected.

Eligibility criteria:
main inclusion: part 1 * independent ethics committee (iec)-approved written informed consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable). * male subject and his female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continue throughout the study period and for 28 days (or 5 half-lives of the study drug whichever is longer) after final study drug administration. * male subject must not donate sperm starting at screening and throughout the study period and for at least 90 days after final study drug administration. * female subject must be either: * post-menopausal (defined as at least one year without any menses) prior to screening, or * premenarchal prior to screening, or * documented surgically sterile or status post hysterectomy (at least 1 month before screening), or * if of childbearing potential, must have a negative urine pregnancy test at screening and must be using highly effective contraception. all females of childbearing potential will be required to use highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and throughout the study period and for 28 days (or 5 half-lives of the study drug whichever is longer) after final study drug administration. * female subject must not be lactating, and must not be breast feeding at screening or during the study period and for 28 days \[or 5 half-lives of the study drug whichever is longer\] after final study drug administration. * female subject must not donate ova starting at screening and throughout the study period and for 28 days \[or 5 half-lives of the study drug whichever is longer\] after final study drug administration. * subject agrees not to participate in another interventional study while on treatment. healthy subjects: * subject must have pre dose egfr values (based on the mdrd method) at screening and day -1 higher or equal to 80 ml/min/1.73 m2. renal impaired subjects: * subject must have pre dose egfr values (based on the mdrd method) at screening and day -1 of 15 to \< 30 ml/min/1.73 m2, 30 to \< 60 ml/min/1.73 m2 or 60 to \< 80 ml/min/1.73 m2 for severe, moderate or mild renal impaired subjects, respectively. part 2 inclusion: * independent ethics committee (iec)-approved written informed consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable). * subject has either known or confirmed t2dm with ckd for at least 1 year \[screening\]. * subject is ≥ 35 and ≤ 80 years of age. * male subject and his female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continue throughout the study period and for 28 days (or 5 half-lives of the study drug whichever is longer) after final study drug administration. * male subject must not donate sperm starting at screening and throughout the study period and for at least 90 days after final study drug administration. * female subject must be either * post-menopausal (defined as at least one year without any menses) prior to screening, or * premenarchal prior to screening, or * documented surgically sterile or status post hysterectomy (at least 1 month before screening), or * if of childbearing potential, must have a negative urine pregnancy test at screening and must be using highly effective contraception1. all females of childbearing potential will be required to use highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and throughout the study period and for 28 days (or 5 half-lives of the study drug whichever is longer) after final study drug administration. * female subject must not be lactating, and must not be breast feeding at screening or during the study period and for 28 days (or 5 half-lives of the study drug whichever is longer) after final study drug administration. * female subject must not donate ova starting at screening and throughout the study period and for 28 days (or 5 half-lives of the study drug whichever is longer\] after final study drug administration. * subject is on a stable therapy with ace inhibitors or arb for at least 3 months \[screening\]. * subject is on a stable anti-hyperglycaemia therapy, e.g. with metformin, sud, tzd or dpp-4 inhibitor. * subject's egfr is between 15-60 ml/min/1.73 m2 (based on the mdrd method). * subject's hba1c level is lower than 7.5% at clinic admission on day -2. * subject has a stable blood pressure for at least 3 to 6 months prior to enrolment. * subject's uacr is higher than 30 mg/g at clinic admission on day -2. part 1 exclusion: all subjects: * female subject who has been pregnant within 6 months before screening or breast feeding within 3 months before screening. * subject has a known or suspected hypersensitivity to asp8232, or any components of the formulation used. * subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). * subject has gilbert's syndrome. * subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to clinic check in. * subject has a history of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to admission to the clinical unit. * subject has a history of drinking more than 21 units of alcohol per week (1 unit = 10 g pure alcohol = 250 ml of beer \[5%\] or 35 ml of spirits \[35%\] or 100 ml of wine \[12%\]) (\> 14 units of alcohol for female subjects) within 3 months prior to admission to the clinical unit. * subject uses drugs of abuse within 3 months prior to admission to the clinical unit. * subject regularly uses any inducer of metabolism (e.g. barbiturates, rifampin ) in the 3 months prior to admission to the clinical unit. * subject had any significant blood loss, donated one unit (450 ml) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to clinic admission on day -1. * subject has positive serology test for hepatitis b surface antigen (hbsag), anti-hepatitis a virus (anti-hav \[igm\]), anti-hepatitis c virus (anti-hcv) or anti- human immunodeficiency virus 1 + 2 (anti-hiv 1+2). * subject participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half-lives whichever is longer, prior to the initiation of screening. * subject is an employee of the astellas group or clinical research organization (cro) involved in the study. healthy subjects: * subject has any of the liver function tests (alanine aminotransferase \[alt\], aspartate aminotransferase \[ast\], total bilirubin \[tbl\]) above the upper limit of normal. in such a case the assessment may be repeated once \[day -1\]. * subject has a mean qtc(f) interval of \> 430 ms (for males) and \> 450 ms (for females) at screening and day -1. if the mean qtc(f) exceeds the limits above, one additional triplicate electrocardiogram (ecg) can be taken. if this triplicate also gives abnormal result the subject should be excluded. * subject uses any prescribed or non-prescribed drugs (including vitamins, hormone replacement therapy, natural and herbal remedies, e.g. st. john's wort) in the 2 weeks prior to study drug administration, except for occasional use of paracetamol (up to 2 g/day). renal impaired subjects: * subject is on or requires hemodialysis or has received a kidney transplantation. * subject has a supine mean systolic blood pressure \ 160 mmhg and a mean diastolic blood pressure \ 100 mmhg, or pulse rate \ 90 beats p/m, on screening and day -1. in such a case the assessment may be repeated once (day -1). * subject has a mean qtc(f) interval of \> 450 ms (for males) and \> 470 ms (for females) at screening and day -1. if the mean qtc(f) exceeds the limits above, one additional triplicate ecg can be taken. if this triplicate also gives abnormal result the subject should be excluded. * subject has not been on a stable dose of allowed concomitant medications for at least 2 weeks prior to day 1 and/or for whom dose changes are likely to occur during the study. * subject requires or is likely to require any new concomitant medications during the course of the study. * subject has obstructive uropathy or other causes of renal impairment not related to parenchymal renal disorder and/or disease of the kidney. * subject has renal disease secondary to malignancy. * subject has a fluctuating or rapidly deteriorating renal function within 4 weeks prior to screening, as indicated by strongly varying or worsening of clinical and/or laboratory signs of renal impairment within the screening period. * subject has any of the liver function tests (alt, ast, tbl) out of range. in such a case the assessment may be repeated once \[day -1\]. * alt or ast \> 2 x upper limit of normal (uln) * tbl \> 1.5 x uln part 2 exclusion * female subject who has been pregnant within 6 months prior to screening assessment or breast feeding within 3 months prior to screening. * subject has known or suspected hypersensitivity to asp8232 or sinistrin, or any components of the formulation used. * subject has participated in part 1 of the 8232-cl-0002 study. * subject has a mean qtc(f) interval of \> 450 ms (for males) and \> 470 ms (for females) at screening and day -2. if the mean qtc(f) exceeds the limits above, one additional triplicate ecg can be taken. if this triplicate also gives abnormal result the subject should be excluded. * subject has a pulse \ 90 bpm; mean systolic blood pressure \>140 mmhg; mean diastolic blood pressure \> 90 mmhg (measurements taken in triplicate after subject has been resting in supine position for 5 min; pulse will be measured automatically) at screening and day -2. in such a case the assessment may be repeated once \[day -2\]. * subject is on or requires hemodialysis or has received a kidney transplantation. * subject has not been on a stable dose of allowed concomitant medications for at least 2 weeks prior to day 1 and/or for whom dose changes are likely to occur during the study. * subject who requires or is likely to require any new concomitant medications during the course of the study. * subject who has obstructive uropathy or other causes of renal impairment not related to parenchymal renal disorder and/or disease of the kidney. * subject who has renal disease secondary to malignancy. * subject who has a fluctuating or rapidly deteriorating renal function within 4 weeks prior to the study, as indicated by strongly varying or worsening of clinical and/or laboratory signs of renal impairment within the screening period. * subject has type 1 diabetes mellitus. * subject with any of the liver function tests (alt, ast, tbl) out of range as indicated below. in such a case the assessment may be repeated once \[day -2\]. * alt or ast \> 2 x uln * total bilirubin \> 1.5 x uln * subject has had myocardial infarct or stroke within 6 months prior to screening. * the subject has gilbert's syndrome. * subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). * the subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within one week prior to clinic admission on day -2. * subject has a history of drinking more than 21 units of alcohol per week (1 unit = 10 g pure alcohol = 250 ml of beer \[5%\] or 35 ml of spirits \[35%\] or 100 ml of wine \[12%\]) (\> 14 units of alcohol for female subjects) within 3 months prior to admission to the clinical unit. * subject uses of drugs of abuse within 3 months prior to admission to the clinical unit. * subject regularly uses any inducer of metabolism (e.g. barbiturates, rifampin) in the 3 months prior to admission to the clinical unit. * subject had any significant blood loss, donated one unit (450 ml) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to clinic admission on day -2. * subject has positive serology test for hbsag, anti hav (igm), anti-hcv or anti-hiv 1+2. * subject participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half-lives whichever is longer, prior to the initiation of screening. * subject is employee of the astellas group or cro involved in the study.

Keywords: asp8232 multiple doses phase 1 single dose